Project Summary Synapses are the basic unit of neuronal communication and most of the excitatory synapses in the vertebrate brain reside on dendritic spines, a type of dendritic protrusion that hosts neurotransmitter receptors and other postsynaptic specializations. Synapses are plastic and undergo short- and long-term modifications during developmental refinement of neuronal circuitry, learning and memory, as well as neurological disorders. The underlying cellular mechanisms that control and regulate these rapid changes in postsynaptic receptors and spine structures remain to be fully elucidated. The cytoskeleton controls many, if not all, aspects of the motility of cellular structures. How the cytoskeleton regulates postsynaptic structure, function, and modifications during plasticity, however, remains poorly understood. The LIM-and-SH3-domain protein 1 (LASP1) is a multi-functional protein that was initially cloned from a cDNA library of metastatic breast cancer cells and its overexpression has been shown to contribute to cancer aggressiveness. LASP1 is highly expressed in the brain and concentrated in the postsynaptic spines, but its function(s) in neurons remain completely unknown. LASP1 is an extremely versatile protein due to its exceptional structure that enables binding to the actin cytoskeleton through its nebulin repeats and, importantly, interacting with multiple signaling pathways through the LIM and SH3 domains. Furthermore, LASP1 can be phosphorylated by cAMP- and cGMP-dependent kinases and tyrosine kinases that regulate its binding to different targets. This proposed study aims to investigate the novel functions of LIM-and-SH3- domain protein 1 (LASP1), a member of the nebulin family, in dendritic spine development and modification during synapse formation and plasticity. Specifically, we will test the novel hypothesis that LASP1 is a novel postsynaptic component that that links multiple signaling cascades to the actin cytoskeleton to regulate postsynaptic spine development and plasticity. Given that many neural disorders are associated with alterations in synaptic connections and plasticity, we hope to gain a better understanding of the molecular and cellular mechanisms underlying synaptic plasticity, which is of importance to our understanding of brain development and functions under both physiological and pathological conditions.